The show follows the daily lives of the Roloff family — parents Matt and Amy, and their four children: Zach, Jeremy, Molly and Jacob. Matt, Amy and Zach are little people, while Jeremy, Molly and Jacob are of average height. Teenagers Zach and Jeremy are fraternal twins; although Zach is not of average height, his brother Jeremy is above average height (6'1"), (185 cm).

The family lives on the 36-acre (150,000 m2) Roloff Farms, located north of Hillsboro in Helvetia, Oregon (a suburb of Portland). Although crops of pumpkins are grown and sold by the family, much of the farm has been converted into a series of playground set pieces for the Roloff children. They were designed by Matt, who spent most of his childhood in the hospital. He has tried to make his children's lives the best possible.

Episodes of the show typically showcase one or more members of the Roloff family engaging in everyday activities such as shopping, athletics and dealing with household finances. The drama of the show arises from the fact that many of these activities are made more challenging due to the height of the dwarfs in the family, as Matt and Amy are 4'1" (124 cm), Zach is 4'4" (132 cm).

As with any reality show, the segments that are aired are ones that are expected to generate viewer interest. However, Little People, Big World avoids portraying the Roloffs in a stereotypical or sensational light. The situations encountered in the show are ones that most families deal with, although the ways in which the Roloffs deal with them are unique to them and are from the perspective of little people.

The Roloffs have several close friends who appear regularly on the show, among them actor Martin Klebba who has known Amy for over 20 years.